Neonatal Apnea

Bodhankar Uday
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Principles of Therapy
Therapy for Apnea can be divided arbitrarily into four groupings based on proposed pathogenic mechanisms that might result in apnea. Institution of interventions should occur in the order of increasing invasiveness and risk. Debate regarding risk of interventions persists, some authors advocating use of methylxanthines prior to CPAP therapy.

Increase Afferent Input into the Respiratory Centers:
- Cutaneous or vestibular stimulation
- Avoid hyperoxia
Treatment of Primary Depression of Respiratory Center:
- Treat infection
- Correct metabolic disturbances
- Administer central nervous system stimulants (aminophylline, theophylline, caffeine, doxapram)
Treatment of Hypoxemia:
- Treat HMD, pneumonia, aspiration, etc.
- Increase inspired oxygen
- Apply continuous positive airway pressure (CPAP)
- Prone positioning
- Treat congestive heart failure
- Close patent ducts arteries
- Transfuse with packed red blood cells
Avoidance of Triggering Reflexes:
- Beware of suction catheters
- Avoid nipple feedings (feed by tube or intravenously)
- Avoid hyperinflation and hyperventilation during bagging
- Avoid cold stimuli to the face
- Place infant in the prone position
- Avoid severe flexion of neck
- Treat gastro esophageal reflux

Institution of interventions should occur in the order of increasing invasiveness and risk.
- Diagnose and treat precipitating causes: respiratory diseases, hypertension, sepsis, anemia, hypoglycemia
- Initiate stimulation (cutaneous, vestibular)
- Initiate a trial of nasal prong air/oxygen airflow
- Initiate a trial of low-pressure nasal continuous positive airway pressure (CPAP)
- Initiate methylxanthine therapy
- Initiate mechanical ventilation

Pharmacologic therapy: The most common drugs used to treat apnea are the methylxanthines: Caffeine and Theophylline (8). Aminophylline is Theophylline combined with Ethylenediamine to increase water solubility.
Mechanism of Action: Methylxanthines block adenosine receptors. Adenosine inhibits the respiratory drive, thus by blocking inhibition, the methylxanthines stimulate respiratory neurons resulting in an enhancement of minute ventilation, chemoreceptor sensitivity to CO2, and cardiac output.
Dosages: The following is a guide to the initiation of medical therapy. Further dosing should be based on drug levels and clinical response. (9,10)

Aminophylline:
Loading dose: 6 mg/kg PO or IV infusion over 30 min
Maintenance dose: 1.5-3 mg/kg/dose IV or PO given q8-12 hr started 8-12 hours after loading dose.
Plasma half life: 20-30 hours
Therapeutic level: 6-13 mcg/ml. Obtain trough 48-72 hours after loading dose.
Toxic level: >20 mcg/ml

Caffeine
Loading dose: 10 mg/kg PO
Maintenance dose: 2.5 mg/kg per dose PO Q24 hours, started 24 hours after the loading dose. Note that doses for caffeine citrate are higher: Use 2X the caffeine base dose.
Plasma half life: 40-230 hrs.
Therapeutic level: 5-25 mcg/ml. Obtain trough level on day 5 or 6 after loading dose.
Toxic level: >40-50 mcg/ml


Apnea TypeType of InterventionTreatment Indication
SpontaneousNo intervention requiredFrequent episodes associated with desaturations (SaO2 <80%) and/or bradycardia (HR <90); e.g., one or more per hour over a long period of time such as 12-24 hours
MildLight touch, stroke back. Associated with desaturations <80% and bradycardia <90Multiple episodes; more than 6 over a 12 hour period or 12 over a 24 hour period
ModerateMove infant, i.e. roll over, reposition, etc.
Oxygen administered
More than 2 episodes in a 24 hour period
SevereProlonged vigorous stimulation. PPV with or without oxygenMore than 1 episode in a 24 hour p

Note: Apnea, bradycardia, and/or cyanotic spells associated with feeding, handling, suctioning, mucus plugging, etc. should not be counted when determining whether to initiate methylxanthine therapy.

Adverse Effects of Methylxanthine Therapy:(11)
- Excessive diuresis
- Increased blood sugar levels
- Increased cerebral metabolic rate (X2-3)
- Increased plasma glycerol
- Decreased anoxic survival in animal studies
- Increased lung glycogen metabolism
- Increased cardiac output
- Decrease cholesterol synthesis in glial cells
- Decreased cerebral blood flow
- Decreased cerebral cell growth and division
- Decreased retinal blood flow

If theophylline therapy fails to reduce the frequency of apneic spells, a trial of the respiratory stimulant doxapram may be considered (12). Doxapram is administered only as a continuous infusion, initially at a rate of 1.0 to 1.5 mg/kg per hour. Once control is obtained, the infusion is decreased. Although increased doses up to 2.5 mg/kg per hour may be effective in infants who continue to have apnea at lower doses, the risk of toxicity is considerably increased.

Toxicity includes hyperactivity, jitteriness, seizure, hyperglycemia, mild liver dysfunction, and hypertension. Although these abnormalities resolve following discontinuation of the drug, toxicity and the need for continuous parenteral administration limit is widespread use.

CPAP is effective in treating both obstructive and mixed apnea, but not central apnea. CPAP is most commonly delivered by nasal prongs or by an endotracheal tube placed in the nasopharynx. Candidates for NCPAP consideration would be infants with moderate to severe apnea i.e. > 8 episodes in a 12 hour period or 2 episodes in 24 hours requiring bag and mask ventilation.

Apnea that continues inspite of optimum methylxanthine treatment may respond to low-level CPAP. Accordingly, a trial of CPAP (4-5 cmH2O) is warranted in addition to or as an alternative to ineffective methylxanthine treatment. Frequent apnea associated with marked bradycardia and/or arterial oxygen desaturation refractory to methylxanthines and/or CPAP should be treated with positive pressure ventilation.

If significant apnea persists despite using both pharmacotherapy and CPAP, the infant should be intubated and ventilated. Initial settings need to be clinically adjusted to prevent episodes of desaturation or cyanosis. In order to minimize barotrauma, short inspiratory times should be used along with minimal peak inspiratory and expiratory pressures. The infant may need to remain on a minimal rate for a few weeks while the respiratory control system matures.

A major issue in the management of infants with apnea is deciding when to stop administration of theophylline and whether or not the infant needs to be discharged on theophylline, a home monitor or both.

Discontinuing medications:- Consider stopping theophylline therapy when the apnea has resolved and the infant weighs between 1800 and 2000 g. If the infants remain asymptomatic following the discontinuation of theophylline therapy, the child may be discharged without further therapy.

Reinstituting medication:- If symptomatic apnea recurs after discontinuing therapy, theophylline therapy should be reinstituted and a decision made to discharge the infant on this medication or to keep the infant hospitalized longer. The use of home monitors in addition to theophylline therapy is controversial. Therapeutic theophylline levels are maintained until the child reaches 52 weeks of post conception age; then theophylline therapy is discontinued and pneumography is performed. If the pneumogram is normal, therapy can be stopped. If the pneumogram is abnormal, the infant needs to be restarted on theophylline and monitoring continued. Another attempt can be made to discontinue theophylline in 4 weeks

Home Monitors:- Preterm infants who continue to exhibit symptomatic apnea when they would otherwise be ready for hospital discharge should have their oxygenation carefully evaluated, because hypoxia can cause apnea in preterm infants, and relieving it may resolve the problem. Chronic lung disease is frequently associated with apnea in preterm infants, In the absence of any identified underlying cause, preterm infants who are still having clinically apparent episodes of apnea can be discharged on home apnea-bradycardia monitoring. If theophylline or caffeine reduces the frequency of these episodes, then these infants can be treated in addition to the home monitor. (13) Routine monitoring of asymptomatic preterm infants, as a group, is not warranted. An additional indication for home monitoring is a positive history of an apparent life- threatening event (ALTE) during the infant's hospital course.


References
Neonatal Apnea Neonatal Apnea 12/19/2001
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